Pyridylthio ketones

ABSTRACT

PYRIDYLTHIO KETONES HAVING THE FOLLOWING STRUCTURAL FORMULA DISCLOSED.   (1-(O=),R&#34;&#34;-PYRID-2-YL)-SO2-(CH2)N-(C(-R)(-R&#39;&#39;))M-CO-   C6H3(-R&#34;)-R&#39;&#39;&#34;   IN THE ABOVE R IS HYDROGEN, LOWER ALKYL OR PHENYL; R&#39;&#39; IS HYDROGEN, LOWER ALKYL OR PHENYL; R&#34; AND R&#34;&#34; MAY BE HYDROGEN, ALKYL, HALO, ALKOXY, ALKYLTHIO, METHYLSULFONYL, METHYLSULFINYL, NITRO AMINO, PHENYL, OR TAKEN TOGETHER TO BE METHYLENEDIOXY OR BENZO; RIV MAY BE HYDROGEN, LOWER ALKYL, HALO, NITRO OR PHENYL. THE SULFUR ATOM MAY BE OXIDIZED TO SULFOXIDE, SULFONE OR NON-OXIDIZED AS THE SULFIDE. THE VALUES FOR M AND N MAY BE 0, 1, 2 OR 3. THESE COMPOUNDS ARE USEFUL AS ANTIFUNGAL AND ANTIBACTERIAL AGENTS. SOME OF THE COMPOUNDS ALSO EXHIBIT ANTISECRETORY AND IMMUNO SUPPRESSANT ACTIVITY. THE PYRIDYLTHIO COMPOUNDS ARE PREPARED BY THE REACTION OF A SALT OF A 2-MERCAPTO PYRIDINE-N OXIDE (II) (M=CATIONIC SPECIES) WITH A SUITABLY SUBSTITUTED COMPOUND III (WHERE X=CHLORO OR BROMO) IN AN   (1-(O=),R&#34;&#34;-PYRID-2-YL)-S-M(+), AND R&#34;-C6H3(-R&#39;&#39;&#34;)-CO-   (C(-R)(-R&#39;&#39;))M-(CH2)N-X -&gt; (1-(O=),R&#34;&#34;-PYRID-2-YL)-S-   (CH2)N-(C(-R)(-R&#39;&#39;))M-CO-C6H3(-R&#34;)-R&#39;&#39;&#34;   APPROPRIATE SOLVENT (SUCH AS WATER, ALCOHOLS, DMSO, DMF, ACETONITRILE, ETC.). THESE REACTIONS ARE USUALLY CARRIED OUT ABOVE ROOM TEMPERATURE AND WHEN COMPLETE, THE PRODUCT IS PRECIPITATED (IF NECESSARY) BY ADDITION OF WATER AND COOLING. OXIDATION OF THE PYRIDYLTHIO COMPOUNS OF TYPE IV WITH PERACIDS SUCH AS M-CHLOROPERBENZOIC, PERFORMIC OR PERACETIC GIVE THE PYRIDYLSULFINYL COMPOUNDS OF TYPE V.   (1-(O=),R&#34;&#34;-PYRID-2-YL)-SO-(CH2)N-(C(-R)(-R&#39;&#39;))M-CO-   C6H3(-R&#34;)-R&#39;&#39;&#34;   OXIDATION OF COMPOUNDS OF TYPE IV WITH AT LEAST TWO MOLES OF OXIDIZING AGENT RESULTS IN THE PREPARATIO OF KETO SULFONES OF TYPE VI. THE SAME COMPOUNDS ARE PREPARED BY THE OXIDATION OF SULFOXIDES OF TYPE V.   (1-(O=),R&#34;&#34;-PYRID-2-YL)-SO2-(CH2)N-(C(-R)(-R&#39;&#39;))M-CO-   C6H3(-R&#34;)-R&#39;&#39;&#34;   THESE COMPOUNDS ARE USEFUL AS ANTI-FUNGAL AND ANTIBACTERIAL AGENTS. SOME OF THE COMPOUNDS ALSO EXHIBIT ANTI-SECRETORY AND IMMUNOSUPPRESSANT ACTIVITY.

United States Patent ABSTRACT OF THE DISCLOSURE Pyridylthio ketones having the following structural formula are disclosed.

R O R" RIV I O (O) I In the above R is hydrogen, lower alkyl or phenyl; R is hydrogen, lower alkyl or phenyl; R" and R may be hydrogen, alkyl, halo, alkoxy, alkylthio, methylsulfonyl, methylsulfinyl, nitro, amino, phenyl, or taken together to be methylenedioxy or benzo; R may be hydrogen, lower alkyl, halo, nitro or phenyl. The sulfur atom may be oxidized to sulfoxide, sulfone or non-oxidized as the sulfide. The values for m and it may be 0, 1, 2 or 3. These com pounds are useful as antifungal and antibacterial agents. Some of the compounds also exhibit antisecretory and immuno suppressant activity.

The 'pyridylthio compounds are prepared by the reaction of a salt of a Z-mercapto pyridine-N oxide (II) (M=cationic species) with a suitably substituted compound III (where X=chloro or bromo) in an appropriate solvent (such as water, alcohols, DMSO, DMF, acetonitrile, etc.). These reactions are usually carried out above room temperature and when complete, the product is precipitated (if necessary) by addition of water and cooling.

Oxidation of the pyridylthio compounds of type IV with peracids such as m-chloroperbenzoic, performic or peracetic give the pyridylsulfinyl compounds of type V.

Oxidation of compounds of type IV with at least two moles of oxidizing agent results in the preparation of keto sulfones of type VI. The same compounds are prepared by the oxidation of sulfoxides of type V.

2 moles IV peracld v E R O R" N WQ 8 0 R! m R!!! These compounds are useful as anti-fungal and antibacterial agents. Some of the compounds also exhibit anti-secretory and immunosuppressant activity.

The present invention is concerned with pyridylthio ketones as well as their sulfones and sulfoxides, having the following structural formula:

wherein R is hydrogen, lower alkyl or phenyl; R is hydrogen, lower alkyl or phenyl; R" and R' are hydrogen, lower alkyl, halo, lower alkoxy, substituted lower alkyl, preferably lower alkyl thio such as methylthio, methylsulfinyl, methylsulfonyl, nitro, amino, phenyl, aralkylalkoxy or taken together to be methylenedioxy or benzo; and R is hydrogen, lower alkyl, halo, nitro or phenyl. The sulfur atom may be oxidized to sulfoxide, sulfone or non-oxidized as the sulfide. The values for m and it may be 0, 1, 2 or 3.

As used in this disclosure, the term lower alkyl is meant to be an aliphatic carbon chain containing 1 to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl and the like.

The above described novel compounds possess potent anti-fungal and anti-bacterial properties. For example, they exhibit anti-fungal activity against the organism Pityrosporum ovale. This organism has been identified as a major cause of dandruff. These compounds have been found active at the concentration of 1-10 [.Lg./1Tl1. against this organism. Further, the activity is comparable to zinc pyrithione, an agent known to be active against this organism. In addition, some of the compounds exhibit antisecretory and immunosuppressant activity as indicated hereinafter. The immunosuppressant activity is comparable to those compounds described in now abandoned US. patent application Ser. No. 39,895. They are to be used in the same manner as the compounds disclosed therein.

In order to use the above compounds, they are formulated with a topically acceptable vehicle such as talc or petrolatum, the active ingredient being present in an amount of about 02-50% by weight. They can also be incorporated into shampoos at the concentration of about 02-50% by weight;

Generally speaking, the above dosage forms containing the active ingredients are applied to the site liberally 1 to 3 times daily. In the case of shampoos, the hair is washed in the usual manner with the shampoo once or twice a week.

3 4 According to the present invention, the above com- VI. The same compounds are prepared by oxidation of pounds are prepared as follows: sulfoxides of type V.

The pyridylthio compounds may be prepared by perzmoles mitting the reaction of a salt of a Z-mercapto pyridine-N N oxide (II) (M=cationic species) with a suitably substituted compound III (where X-chloro or bromo) in an In order to further illustrate the practice of this invention, the following examples are given.

I R o R" EXAMPLE 1 0 IV I g appropriate solvent (such as water, alcohols, DMSO, S CH Br DMF, acetonitrile, etc.). These reactions are usually J carried out above room temperature and when complete, the product is precipitated (if necessary) by addition of 4'-bromo-2-(2-pyridylthio)acetophenone N-oxide Water and cooling A mixture of 34.9 g. (0.234 mole) of the sodium salt Oxidation of the pyridylthio compounds of type IV with peracids such as m-chloroperbenzoic, performic or of z'mercaptopyndme N'oxlde and 62 (0'223 mole) of p-bromophenacyl bromide in 400 ml. of methanol was pal-acetic give the pyridylsulfinyl compounds of type refluxed for 7 hr. and filtered. Additional solid was obtained from concentration of the filtrate. The combined Iv EL R 0 p." 3 solids were washed with water and recrystallized from S (CHI) A. E methanol to constant melting point, 186-187.5. The

N 1 1 total yield was 69 g. 0.213 mole, 95.0%

g 0 m Analysis.-Calcd. for C H NO BrS (percent): C,

48.16; N, 4.32; S, 9.89; Br, 24.65. Found (percent): C, 48.29; H, 3.24; N, 4.35; S, 10.00; Br, 24.36. Oxidation of compounds of type 'IV with at least two By analogous procedures, utilizing the appropriate halo moles of oxidizing agent, e.g., the above-mentioned per- 'ketones, were prepared the additional compounds listed acids, results in the production of keto sulfones of type in Table I.

TABLE I R N 1 ll 0 0 Ca1ed., percent Found, percent X R M.P. Molecular formula C H N C H N OH, H 133-135 CHHIINSOI 03.05 4.52 5.71 03.07 4.50 5.02 GB: 4-01 174-175 cnHmoiNsop 55.82 3.00 5.01 55.80 3.53 4.98 CH, 4-F 194-190 CisHmFNSO: 59.30 3.83 5.32 59.01 3.81 5.20 0H, 3,4-(0H): 252-253 C15H11Ns0l 55.31 4.00 5.05 55.15 4.10 5.02 0H, 2,4-(0114), 106-108 ClfiHlaNSOl 05.91 5.53 5.12 55.73 5.50 4.98 0H, 4-0011. 139-141 011H15Ns01 51.07 4.70 5.09 01.00 4.73 4.99 CH, 4- -101 C19H15NSO| 71.01 4.70 4.30 71.15 4.09 4.35 0H, 4-00H45 -111 CaoHnNSOs 08.30 4.88 3.99 08.38 4.07 3.80

OH: H 99-100 C14H13NS0| 04.84 5.05 5.40 04.50 4.97 5.18 -CH 111. 4-OCH; 91-93 CnHuNSO: 52 20 5 23 -11 08 02.08 5 20 11 18 CH.

1 OH H 147-148 CIOHIBNSOI 71.01 4.70 4.30 70.90 4.74 4.11 -CH4CH9- H -148 CuHiaNSOr 04.84 5.05 5.40 04.72 5.10 5.14 -CHzCH4- 401 150-158 C14H11C1NSO: 57.24 4.12 4.77 57.28 4.10 4.01 CHCH5- 4-Br 159-171 C14HnBrNSO 49.72 3.58 4.14 49.80 3.50 4.10 -cH,0H,- 4-F 174-175 O14H19FNSO9 50.04 4.35 5.05 00.74 4.41 5.07 CHCH4 4-ooH, 157-158 clsHlsNsos 02.20 5.23 4.84 02.29 5.22 4.74 (CH9)a H 80-88 CHHMNSO: 05.91 5.53 5.12 05.52 5.53 4.92 (CHa)a 4-Br 120-121 CmHuBrNSOg 51.15 4.01 3.98 51.27 4.10 3.94 -(CH,) 4-F 113-114 CMHHFNSOI 01.84 4.84 4.81 52.12 4.08 4.01 -0H= 3,4-benzo 159-171 CuHuNOzS 09.13 4.44 4.74 09.00 4.35 4. 01 -0H,-cH, 4-SCH1 101-103 ouHwNois, 58.99 4.95 4.59 59.25 5.04 4.50 CH-,-CH; 45040111 187-188 C16H15NO4S1 53.40 4.48 4.15 53.28 4.57 4.08

3111 H 79-81 CnHuNmS- 05.91 5.53 5.12 55.93 5.45 5.00 CI.

Also exhibits immun0uppressant activity. Decomposes.

9 Sulfur analysis.

EXAMPLE 2 4-bromo-2-(Z-pyridylsulfinyl)acetophenone N-oxide To a solution of 8.1 g. (0.025 mole) of 4'-bromo-2-(2- pyridylthio)acetophenone N-oxide in 1 l. of methylene chloride cooled in ice-water was added 5.47 g. (0.026 mole) of 83% m-chloroperbenzoic acid. The mixture was gradually warmed to room temperature and was stirred for 3 hours. The solution was washed with aqueous sodium bicarbonate and water, was dried and concentrated to give 4.5 g. (0.0135 mole, 52.9%) of a solid material. The solid was recrystallized from methanol-water to constant melting point, 180.5181.5.

Analysis.Calcd. for C H NO BrS (percent): C, 45.90; H, 2.96; N, 4.12; S, 9.42; Br, 23.49. Found (percent): C, 46.14; H, 2.97; N, 3.94; S, 9.23; Br, 23.70.

By analogous procedures, utilizing the appropriate thio ketones, were prepared the compounds listed in Table II.

6 solution was washed with aqueous sodium bicarbonate and water, was dried and concentrated to give 10.3 g. (96%) of a solid which was recrystallized from ethanol, melting point, 159-61.

Analysis.--Calcd. for C H NO BrS (percent): C, 43.83; H, 2.83; N, 3.93; S, 9.00; Br, 22.43. Found (percent): C, 44.1-0; H, 2.84; N, 3.71; S, 9.00; Fr, 22.31.

EXAMPLE 4 4-phenyl-2- (2-pyridylsulfonyl) acetophenone N -oxide TABLE II l H O 0 Calcd., percent Found, percent X R M.P. Molecular formula C H N C H N CH; 401 177-179 ClaHtoClNSOz 52. 80 3. 41 4. 74 52. 93 3. 41 4. 57 CH; 4-F 150-152 CtaHwFNSOa 55. 91 3. 61 5. 02 55. 84 3. 62 4. 90 (3H, 2,4-(CH;)1 153- 155 GisHnNSOz 62. 26 5. 23 4 84 62. 28 5. 30 4. 87 CH 4-0 0H; 170-172 OnHmNS04 57. 72 4. 4. 81 57. 54 4. 43 4. 72 OH 4- I 153-154 CmHtaNSO: 67. 64 4. 48 4. 15 67. 55 4. 51 3. 94 CH, 40 CH9 202 203 CzuHnNSO; 65. 38 4. 66 3. 81 65. 29 4. 56 3. 94

OH; H 136-137 CuHuNSOs 61. 07 4. 76 5. 09 60. 79 4. 74 5. 03

CH: 4-0CH: 132-133 CuHrsNSOt 59. 00 4. 95 4. 59 58. 63 4. 95 4. 37

%H 11 160-162 CNHHNSO; 67. 64 4. 48 4. 15 67. 86 4. 38 3. 98 --(CH H 128-130 C H NSOi 61. 07 4. 76 5. 09 61. 18 4. 5. 07 -(CH2)2 4-01 134-135 OuHrzClNSOa 54. 28 3. 4. 52 54. 27 3. 85 4. 72 -(OH2)2 4-F 120-121 CltHiaFNSOa 57. 33 4. 12 4. 78 56. 97 4. 09 4. 65 --(CHz)2 4-OCH3 113-114 C15H15NSO4 59. 00 4. 4. 59 58. 95 4. 92 4. 42 -(CH2)a- H 156-158 Cid-115N801 62. 26 5. 23 4. 84 62. 48 5. 25 4. 68 -(CHz)a- 4-Br 137-139 C15H14BINSOa 48. 92 3. 83 3. 80 48. 72 3. 87 3. 66 (CH 41* -136 CisHnFNSOi 58. 62 4. 59 4. 56 58. 37 4. 59 4. 62 CH2 3,4-benzo 74-76 C17H13NO2S 69. 13 4 43 4. 74 69. 01 4. 45 4 62 CH2OH 4-SOH 129-131 C15H15N08S2 56. 05 4. 70 4. 36 56. 26 4. 85 4. 18

Also exhibits immunosuppressant activity. b Decomposes.

EXAMPLE 3 4-bromo-2- (2-pyridylsu1fonyl acetophenone N-oxide To a mixture of 0.02 mole of 4'-phenyl-2-(2-pyridylsulfinyl)acetophen0ne N-oxide in 200 ml. of CH Clwas added in ca. 10 portions over 2 hrs. with stirring, 0.06 mole of m-chloroperbenzoic acid. The mixture was stirred for an additional 2 hrs., 300 ml. of CH Cl added and the organic phase was extracted with saturated aq. NaHCO; and dried over anh. MgSO Removal of solvent and trituration of residue with cold methanol yielded 90% of It. tan product. Several recrystallizations from 4:1 EtOHzDMF (Florisil) gave colorless crystals, MP. 148- 188.

Analysis.-Calcd. for C H NSO (percent): S, 65.58; H, 4.28; N, 3.96; S, 9.07. Found (per-cent): C, 64.66; H, 4.33; N, 4.07; S, 9.03.

TABLE III 8. A compound according to claim 1 wherein n is 2, m is 0, R=R =H and R'=p-methoxy.

R sm-oo-o-Q Calcd., percent Found, percent X R M.P. Molecular formula C H N C H N CH2 H 134-135 C1|HnNSO4 56. 31 4. 00 11. 56 56. 29 4. 05 11. 59 CH; 4-1? 138-139 CnHioFNSOv 52. 88 3. 41 4. 74 52. 57 3. 57 4. 59 CH: 4-0 CH: 114-116 Ol4Hl3FNSO5 54. 72 4. 26 4. 56 54. 85 4. 55 4. 86 CH: 2,4-(011 150-151 CHi5NSO4 59. 00 4. 95 4. 59 58. 83 4. 98 4. 52

OH: H b 185-186 CHHHNSOA 57. 72 4. 50 4. 81 57. 50 4. 45 4. 54 5 (IIH; 4-0 CH; 162-164 CisHisNSOr 56.06 4. 71 4. 36 55. 82 4. 71 4. 22

3 H H 198-199 CnHrsNSOr 64. 58 4. 28 3.96 64. 63 4. 43 3. 72 (CHz) z- H 177-179 CHHISNSOP 57. 72 4. 50 4. 81 57. 92 4. 58 4. 76 CH2) z- 4-Cl 140-142 CiiHiaClNSOr 51. 62 3. 71 4. 30 51. 54 3. 68 4. 15 -(CH2) 2- 4-]? 182-184 C14Hi-2FNSO4 54. 36 3.91 4. 53 54. 61 3. 86 4.26 (CH2) 2- 4-0 CH; 146-148 CisHisNSOi 56. 06 4. 71 4. 36 55. 77 4. 73 4. 16 -(CH2) a- H 112-114 ClsHraNSOr 59. 00 4. 95 4. 59 58. 91 5. 02 4. 46 CH2) 4-Br 128-130 CrsHuBrNSOr 46. 89 4. 67 3. 65 47. 03 3. 68 3. 56 -(C H2) s- 4-1 133-134 CHHHFNSOA 55. 72 4. 36 4. 33 55. 91 4. 53 4. 50 Hz- 3,4-benzo 143-145 CnHuNOaS 65. 58 4. 21 4. 50 65. 29 4. 15 4. 73 CHCH 4-8 CH3 173-175 Cl5Hl5NO4S2 53. 40 4. 48 4. 15 53. 4. 67 3. 97 -CHzCHz 4-SOzCH: 180-181 CtsHisNOoSa 48. 77 4. 09 3. 79 48. 98 4. 18 4. 02

I Also exhibits lmmunosuppressant activity. Decomposes. Sulfur analysis.

EXAMPLE 5 A typical shampoo composition is prepared by mixing together the following ingredients in water:

Homologues of dibasic aliphatic acid esters, available under the trade name Stanapol SH-IOO active) from Standard Chemical Products, ml. 25 30% active sodium lauryl sulfate, ml. 25 Compound of Example 1, grams 2 Water to make, 100 ml.

Other compounds of this invention are also prepared as shampoos in the same manner as described.

We claim:

1. A compound of the formula:

wherein R is hydrogen, lower alkyl or phenyl; R is hydrogen, lower alkyl or phenyl; R and R are each hydrogen, alkyl, having 1 to 6 carbon atoms, halo, loweralkylthio, phenyl lower alkoxy lower alkoxy, in which alkoxy has from 1 to 6 carbon atoms, nit-r0, amino, phenyl, or taken together to form benzo; R is hydrogen and m and n have a value of 0, 1, 2 or 3.

2. A compound according to claim 1 wherein n is 1, m is 0, R'=R "==H and R""=p-methoxy.

3. A compound according to claim 1 wherein n is 1, m is 0, R=R "-=H and R"-=p-chloro.

4. A compound according to claim 1 wherein n is 2, m is 0, R"=R"' =R =H.

5. A compound according to claim 1 wherein n is 2, m is 0, R"=R =H and R is p-bromo.

6. A compound according to claim 1 wherein n is 2, m is 0, R"-=R =H and R'=p-chloro.

7. A compound according to claim 1 wherein n is 2, m is 0, R =R =H and R'-" =p-fluoro.

RI m R!!! wherein R is hydrogen, lower alkyl or phenyl, R is hydrogen, lower alkyl, having 1 to 6 carbon atoms, or phenyl, R" and R' are each hydrogen, lower alkyl, halo, lower alkylthio, phenyl lower alkoxy, lower alkoxy, in which alkoxy has from 1 to 6 carbon atoms, nitro, amino, phenyl, or taken together to form benzo, R is hydrogen and m and n have a value of 0, 1, 2 or 3.

15. A compound according to claim 14 wherein n=0, m=1, R-=CH R"=R=R"'=R =H.

16. A compound according to claim 14 wherein n=1, m=0, R"=R =H and R" =p-bromo.

17. A compound according to claim 14 wherein n=2, m=0 and R"=R"'=R =H.

18. A compound according to claim 14 wherein n=2, m=0, R"'=R =H and R" =p-chloro.

19. A compound according to claim 14 wherein n=2, m=0, R"=R =H and R' =p-bromo.

20. A compound according to claim 14 wherein n=2, m=0, R"=R =H and R =p-fiuoro.

21. A compound according to claim 14 wherein n=2, m=0, R=R =H and R"=p-methoxy.

22. A compound according to claim 14 wherein n=2, m =0, R" =R =H and R"=p-methylthio.

23. A compound according to claim 14 wherein n=3, m=0, 4"=R =H and R=p-fluoro. 24. A compound of the formula:

wherein R is hydrogen, lower alkyl or phenyl, R is hydrogen, lower alkyl, having 1 to 6 carbon atoms, or phenyl, R" and R are each hydrogen, lower alkyl, halo, lower alkylthio, phenyl lower alkoxy, lower alkoxy, in which alkoxy has from 1 to 6 carbon atoms, nitro, amino, phenyl, or taken together to form benzo, R is hydrogen and m and n have a value of 0, 1, 2 or 3.

25. A compound according to claim 24 wherein n: 1, m =0 and R"=R"' =R :=H.

26. A compound according to claim 24 wherein n=1, m=0, R"=R =H and R"=p-fiuoro.

27. A compound according to claim 24 wherein n: 1, m=0, R"-=R =H and R"=p-phenyl.

28. A compound according to claim 24 wherein n: 1, m=0, R"'=R =H and R"'=2,4-dimethyl.

29. A compound according to claim 24 wherein n=2, m=0, R:=R""=R =H.

30. A compound according to claim 24 wherein n=2, m=0, R=R =H and R"=p-chloro.

31. A compound according to claim 24 wherein n=2, m=0, R" =R =H and R"=p-fluoro.

32. A compound according to claim 24 wherein n=3, m =0, R"=R -=H and R"=p-fluoro.

33. A compound according to claim 24 wherein n=0, m=1, R =Q) and R=R"-=R=R =H.

References Cited Djerassi, Carl et al.: The Reaction of a-Halo Ketones With Z-Pyridine-Thiol, Apr. 7, 1954, J. Amer. Chem. Soc., vol. 76, pp. 4470 4472.

Fieser, Louis et al.: Advanced Organic Chemistry, 1962, pp. 312 and 313.

HENRY R. JILES, Primary Examiner M. A. M. CROWDER, Assistant Examiner U.'S. Cl. X.R. 

